Transcript How Do you Grow Old Successfully? Have Good Genes in a Good

How Do you Grow Old Successfully?
Have Good Genes in a Good Environment in
Early Life.
April 6, 2007
A.J. Kahn
Berkeley, CA
Can single genes affect lifespan?
2x
Note: In the nematode gene manipulation has
yielded animals that live 5x longer!
NIA/NIH - 2003
How heritable is human longevity?
Genetic Heritability of Human Lifespan
Cournil & Kirkwood 2001
Twin Studies
McGue et al (1993)
Herskind et al (1996)
Ljungquist et al (1998)
0.22
0.25
<0.33
Traditional Family Studies
Philippe (1978)
0-0.24
Bocquet-Appel & Jakobi (1990)
0.10-0.30
Mayer (1990)
0.10-0.33
Gavrilova et al (1998)
0.18-0.58
Cournil et al (2000)
0.27
Genes account for 25% of what determines longevity
If genetics, per se, only play a 25% role in determining
human longevity, then the balance of the critical factors
affecting lifespan must reside in the environment.
The Good News - much of our longevity (and healthy aging)
is, at least potentially, under our control.
Lifestyle choices - diet, preventive medicine, non-smoking,
exercise, avoiding unsafe behavior.
Gene-environment Interactions are
very important.
Most birth defects (~65%) and probably
most clinical problems arise as a
consequence of gene-environment
interaction.
Chakravarti & Little, Nature 421, 2003
Caloric Restriction - the best established illustration of environmental
intervention that affects longevity.
LE Magazine June 2003
An additional ‘take-home’ lesson
Extended lifespan achieved by genetic alteration or
environmental manipulation almost always equates, at
least in a laboratory environment, to a reduced
incidence potentially fatal diseases (e.g. cancer), slower
onset of age-related senescent changes (loss in
cognitive ability, slower mobility, greater fragility) and, of
course, increased longevity.
Concerns: impact on retirement infrastructure,
medical care, workforce ‘turnover’, and economy.
Will CR work in Humans?
Given the extended lifespan in humans,
is it possible to answer this question?
Alternative Measures
 In many cases, ‘biomarkers’ (physiological/ or
pathophysiologcal indicators of aging) are used instead of
lifespan as a measure of a genetic or environmental effect
on lifespan.
 Additionally, increased risk or incidence of conditions
that predispose to higher morbidity and mortality will also
be used as an indirect assessment of factors that affect
healthy aging and likely longevity.
Some
Candidate
‘Biomarkers’
*
* Keep in mind for metabolic syndrome
Heilbronn and Ravussin, 2003
Recent Findings
Temperature
Insulin
Human study at
6 months postIntervention.
Heilbronn et. al. 2006
Something for the future?
Caloric Restriction Mimetics:
Agents that will duplicate or mimic the action of
CR without the heavy, almost certainly unrealistic
commitment to years of significant dieting.
(A related strategy - use of oxidative damage control mimetics
(e.g., catalase/superoxide dismutase) that will augment natural
resistance to oxidative stress and consequent damage.)
Is there a relationship between early development and
aging and lifespan?
Do events that occur in utero and early in
postnatal life also affect lifespan?
Might such events also increase the risk of
morbidity in adult life and, therefore at least
indirectly, longevity?
More Suggestive Evidence: Even Month
of Birth May Affect Longevity
Month of Birth Predicts the US Life Expectancy at Age 80
Computed using the Social Security Administration data
7.9
life expectancy at age 80, years
1885 Birth Cohort
1891 Birth Cohort
Source:
Gavrilova, N.S.,
Gavrilov, L.A. Search
for Predictors of
Exceptional Human
Longevity. In: “Living
to 100 and Beyond”
Monograph. The
Society of Actuaries,
Schaumburg, Illinois,
USA, 2005, pp. 1-49.
7.8
7.7
7.6
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Month of Birth
Multiple Factors May Affect Adult Disease Risk
Gluckman and Hanson, 2004
Epigenetics (‘above the genome’): Circumstance in which
gene function is altered stably but without fundamental
change, e.g.,by mutation, deletion, rearrangement, in
primary
DNA structure.
Epigenesis typically (always?) occurs via alterations in
chromatin structure (e.g., modification in histone structure)
or secondary changes in DNA, e.g., DNA methylation). DNA
methylation, for example, is associated with a reduction in
gene expression.
DNA methylation
Histone modification
Hill, 2006
Vitamin supplements to mothers -> darker, smaller
less obese pups (folic acid, vitamin B12, choline and betaine ->
increased DNA methylation.)
Cohen, 2003 after Jirtle
Changes in DNA
methylation occur
over a lifetime and
help to explain the
differences between
identical twins and the
divergence observed
in individual humans
and animals as they
age.
Fraga et. al., 2005
Nutritional Factors Affecting Human Offspring
Folate = folic
acid
Johnson-Zeigler, 2006
Postnatal diet can also affect lifespan
Ozanne & Hales, 2004
Maternal; behavior Can Also Effect Epigenetic Change
Increased grooming -.> altered DNA methylation/histone acetylation GC receptor
In brain (hippocampus) ->altered stress resistance.
Nature Neuroscience, 2004
The obesity epidemic
CDC
The problem only gets worse with age
Age-specific prevalence of the metabolic syndrome among 8814 US adults
U. Laval, 2004
Dutch Famine WW II
Olson, 2004
Obesity as consequence of malnutrition in utero
Olson, 2004
Barker Hypothesis
Prenatal events establish lifelong
physiological patterns that may manifest
as disease processes in later life
-David Barker, FRS, University of Southampton
The consequence of poor maternal malnutrition and
the fetus is likely intrauterine growth retardation
leading to low birth weight.
Why is Low Birth Weight Important?
•Prematurity- immature organ systems
–In particular lungs- lack of surfactant
•Leads to respiratory distress syndrome
–Inadequate fat stores
•Inability to maintain body temperature
•Low birth weight for age- predisposition to
cardiovascular disease, hypertension and NIDDM
in adult life- concept of ‘intrauterine programming’
and the concept of the ‘thrifty hypothesis’.
Olson, 2004
Some examples of effects low birth weight in adults
Gluckman & Hanson. 2004
Still more examples
G.M. England, 2003
The ‘Thrifty Phenotype”
A ‘mismatch’ between
the in utero ‘programming’
to conserve nutritional
resources, e.g. fat storage,
(as a consequence of poor
maternal nutrition) and an
abundance of food in postnatal life.
McCarthy, 1998
Lau & Rogers, 2004,
Fetal Programming
Metabolic syndrome is characterized by obesity, diabetes
(insulin resistance) and an increased incidence of CVD.